Tertiary amino compounds having opioid receptor affinity

ABSTRACT

Disclosed are compounds of the formula (I)  
                 
 
     wherein R 1 , R 2  R 3  R 4  R 5 , R 6  and N are as disclosed herein. The compounds are useful for the treatment of chronic and acute pain.

[0001] This application claims the benefit of U.S. provisional No.60/169,396 filed Dec. 6, 1999, the disclosure of which is herebyincorporated by reference.

BACKGROUND OF THE INVENTION

[0002] Chronic pain is a major contributor to disability in theindustrialized world and is the cause of an untold amount of suffering.The successful treatment of severe and chronic pain is a primary goal ofthe physician with opioid analgesics being the current drugs of choice.Unfortunately, this class of compounds produces several undesirable sideeffects including respiratory depression, constipation, and thedevelopment of tolerance and dependence.

[0003] Opioids are derived from the opium poppy papaya somniferum andinclude drugs such as morphine, codeine and semi-synthetic compoundsderived from them and from thebaine, another component of the opiumpoppy. It was hypothesized that the opioids derived their therapeuticeffect by interacting with specific receptor sites in the body. Laterexperiments led to the belief that there were more than one receptorsite in the body, in explanation for the fact that the syntheticcompound nalorphine provides analgesic activity while at the same time,antagonizes the analgesic effect of morphine.

[0004] Until recently, there was evidence of three major classes ofopioid receptors in the central nervous system (CNS), with each classhaving subtype receptors. These receptor classes were designated as μ, δand k. As opiates had a high affinity to these receptors while not beingendogenous to the body, research followed in order to identify andisolate the endogenous ligands to these receptors. These ligands wereidentified as enkephalins, endorphins and dynorphins.

[0005] Recent experimentation has led to the identification of a cDNAencoding an opioid receptor-like (ORL1) receptor with a high degree ofhomology to the known receptor classes. This newly discovered receptorwas classified as an opioid receptor based only on structural grounds,as the receptor did not exhibit pharmacological homology. It wasinitially demonstrated that non-selective ligands having a high affinityfor μ, δ and k receptors had low affinity for the ORL1. Thischaracteristic, along with the fact that an endogenous ligand had notyet been discovered, led to the term “orphan receptor”.

[0006] The science relating to opioid receptors presents an opportunityin drug discovery for novel compounds which can be administered for painmanagement or other syndromes modulated by these receptor. Such drugdiscovery could lead to compounds having a higher affinity for the μ, δand k receptors than known compounds, while producing less side effects.

OBJECTS AND SUMMARY OF THE INVENTION

[0007] It is accordingly an object of the present invention to providenew compounds which exhibit affinity for opioid receptors.

[0008] It is another object of the present invention to provide newcompounds which exhibit affinity for the opioid μ receptor.

[0009] It is another object of the present invention to provide newcompounds for treating a patient suffering from chronic or acute pain byadministering a compound having affinity for the opioid μ receptor.

[0010] It is another object of the invention to provide new compoundswhich have agonist activity at the μ receptor which is greater thancompounds currently available e.g. morphine.

[0011] It is another object of the invention to provide methods oftreating chronic and acute pain by administering compounds which haveagonist activity at the μ receptor which is greater than compoundscurrently available.

[0012] It is another object of the invention to provide methods oftreating chronic and acute pain by administering non-opioid compoundswhich have agonist activity at the μ receptor and which produce lessside effects than compounds currently available.

[0013] It is another object of the invention to provide a method ofreducing side effects associated with the administration of opioidanalgesics in a human patient comprising administering to said humanpatient an analgesically effective amount of a non-opioid compound whichexhibits a binding affinity specificity for the μ receptor as comparedto the δ₂ receptor (K_(l) (nM) at the δ₂ receptor/K_(l) (nM) at the μreceptor) of greater than about 250.

[0014] It is another object of the present invention to providecompounds useful as analgesics, antiinflammatories, diuretics,anesthetics and neuroprotective agents and methods for administeringsaid compounds.

[0015] Other objects and advantages of the present invention will becomeapparent from the following detailed description thereof. With the aboveand other objects in view, the present invention comprises compoundshaving the general formula (I):

[0016] wherein

[0017] R₁ is selected from the group consisting of a bond and C₁₋₁₀alkyl, alkenyl or alkenylene;

[0018] R₂ and R₃ are independently selected from the group consisting ofhydrogen and C₁₋₁₀ alkyl, alkenyl or alkenylene

[0019] R₄ is selected from the group consisting of a bond and C₁₋₁₀alkyl, alkenyl or alkenylene, said C₁₋₁₀ alkyl, alkenyl or alkenyleneoptionally substituted with 1-3 halogen or oxo groups;

[0020] R₅ is selected from the group consisting of hydrogen, a 5 or 6membered aromatic or heteroaromatic group, and a C₃₋₁₂ cycloalkyl;

[0021] R₆ is selected from the group consisting of C₁₋₁₀ alkyl, C₃₋₁₂cycloalkyl and halogen; and

[0022] N is an integer from 0-3; and pharmaceutically acceptable saltsthereof.

[0023] In preferred embodiments R₁ is selected from methyl or ethyl.

[0024] In other preferred embodiments R₂ is selected from methyl, ethyl,propyl and butyl.

[0025] In other preferred embodiments R₄ is selected from a bond, methylor ethyl, wherein the methyl and ethyl are optionally substituted withan oxo group.

[0026] In other preferred embodiments R₅ is a 6-membered aryl ring,preferably phenyl.

[0027] As used herein, the term “alkyl” means a linear or branchedsaturated aliphatic hydrocarbon group having a single radical and 1-10carbon atoms. Examples of alkyl groups include methyl, propyl,isopropyl, butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and pentyl.A branched alkyl means that one or more alkyl groups such as methyl,ethyl or propyl, replace one or both hydrogens in a —CH₂— group of alinear alkyl chain.

[0028] The term “cycloalkyl” means a non-aromatic mono- or multicyclichydrocarbon ring system having a single radical and 3-12 carbon atoms.Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclopentyl,and cyclohexyl. Exemplary multicyclic cycloalkyl rings include adamantyland norbornyl.

[0029] The term “alkenyl” means a linear or branched aliphatichydrocarbon group containing a carbon-carbon double bond having a singleradical and 2-10 carbon atoms. A “branched” alkenyl means that one ormore alkyl groups such as methyl, ethyl or propyl replace one or bothhydrogens in a —CH₂— or —CH═ linear alkenyl chain. Exemplary alkenylgroups include ethenyl, 1- and 2-propenyl, 1-, 2- and 3-butenyl,3-methylbut-2-enyl, 2-propenyl, heptenyl, octenyl and decenyl.

[0030] The term “cycloalkenyl” means a non-aromatic monocyclic ormulticyclic hydrocarbon ring system containing a carbon-carbon doublebond having a single radical and 3 to 12 carbon atoms. Exemplarymonocyclic cycloalkenyl rings include cyclopropenyl, cyclopentenyl,cyclohexenyl or cycloheptenyl. An exemplary multicyclic cycloalkenylring is norbomenyl.

[0031] The term “aryl” means a carbocyclic aromatic ring systemcontaining one, two or three rings which may be attached together in apendent manner or fused, and containing a single radical. Exemplary arylgroups include phenyl and naphthyl.

[0032] The term “heteroaryl” means unsaturated heterocyclic radicals,wherein heterocyclic is as previously described. Exemplary heteroarylgroups include unsaturated 3 to 6 membered heteromonocyclic groupscontaining 1 to 4 nitrogen atoms, such as pyrrolyl, pyridyl, pyrimidyl,and pyrazinyl; unsaturated condensed heterocyclic groups containing 1 to5 nitrogen atoms, such as indolyl, quinolyl, isoquinolyl; unsaturated 3to 6-membered heteromonocyclic groups containing an oxygen atom, such asfuryl; unsaturated 3 to 6 membered heteromonocyclic groups containing asulfur atom, such as thienyl; unsaturated 3 to 6 memberedheteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3nitrogen atoms, such as oxazolyl; unsaturated condensed heterocyclicgroups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such asbenzoxazolyl; unsaturated 3 to 6 membered heteromonocyclic groupscontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such asthiazolyl; unsaturated condensed heterocyclic group containing 1 to 2sulfur atoms and 1 to 3 nitrogen atoms, such as benzothiazolyl. The term“heteroaryl” also includes unsaturated heterocyclic radicals, whereinheterocyclic is as previously described, in which the heterocyclic groupis fused with an aryl group, in which aryl is as previously described.Exemplary fused radicals include benzofuran, benzdioxole andbenzothiophene.

[0033] As used herein, the term “patient” includes both human and othermammals.

[0034] As used herein, the term “halogen” includes fluoride, bromide,chloride, iodide or alabamide.

[0035] As used herein, the term “specificity” with respect to opioidreceptors is obtained by dividing the K_(l) (nM) at one opioid receptorby the K_(i) (nM) at another receptor (higher K_(l)/lower K_(i).

[0036] The invention disclosed herein is meant to encompass allpharmaceutically acceptable salts thereof of the disclosed compounds.The pharmaceutically acceptable salts include, but are not limited to,metal salts such as sodium salt, potassium salt, secium salt and thelike; alkaline earth metals such as calcium salt, magnesium salt and thelike; organic amine salts such as triethylamine salt, pyridine salt,picoline salt, ethanolamine salt, triethanolamine salt,dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt and the like;inorganic acid salts such as hydrochloride, hydrobromide, sulfate,phosphate and the like; organic acid salts such as formate, acetate,trifluoroacetate, maleate, tartrate and the like; sulfonates such asmethanesulfonate, benzenesulfonate, p-toluenesulfonate, and the like;amino acid salts such as arginate, asparginate, glutamate and the like.

[0037] The invention disclosed herein is also meant to encompass allprodrugs of the disclosed compounds. Prodrugs are considered to be anycovalently bonded carriers which release the active parent drug in vivo.

[0038] The invention disclosed herein is also meant to encompass the invivo metabolic products of the disclosed compounds. Such products mayresult for example from the oxidation, reduction, hydrolysis, amidation,esterification and the like of the administered compound, primarily dueto enzymatic processes. Accordingly, the invention includes compoundsproduced by a process comprising contacting a compound of this inventionwith a mammal for a period of time sufficient to yield a metabolicproduct thereof. Such products typically are identified by preparing aradiolabelled compound of the invention, administering it parenterallyin a detectable dose to an animal such as rat, mouse, guinea pig,monkey, or to man, allowing sufficient time for metabolism to occur andisolating its conversion products from the urine, blood or otherbiological samples.

[0039] The invention disclosed herein is also meant to encompass thedisclosed compounds being isotopically-labelled by having one or moreatoms replaced by an atom having a different atomic mass or mass number.Examples of isotopes that can be incorporated into the disclosedcompounds include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O,¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively. Some of the compoundsdisclosed herein may contain one or more asymmetric centers and may thusgive rise to enantiomers, diastereomers, and other stereoisomeric forms.The present invention is also meant to encompass all such possible formsas well as their racemic and resolved forms and mixtures thereof. Whenthe compounds described herein contain olefinic double bonds or othercenters of geometric asymmetry, and unless specified otherwise, it isintended to include both E and Z geometric isomers. All tautomers areintended to be encompassed by the present invention as well.

[0040] As used herein, the term “stereoisomers” is a general term forall isomers of individual molecules that differ only in the orientationof their atoms in space. It includes enantiomers and isomers ofcompounds with more than one chiral center that are not mirror images ofone another (diastereomers).

[0041] The term “chiral center” refers to a carbon atom to which fourdifferent groups are attached.

[0042] The term “enantiomer” or “enantiomeric” refers to a molecule thatis nonsuperimposeable on its mirror image and hence optically activewherein the enantiomer rotates the plane of polarized light in onedirection and its mirror image rotates the plane of polarized light inthe opposite direction.

[0043] The term “racemic” refers to a mixture of equal parts ofenantiomers and which is optically inactive.

[0044] The term “resolution” refers to the separation or concentrationor depletion of one of the two enantiomeric forms of a molecule.

[0045] Certain preferred compounds according to the invention include:

[0046] 1-benzylamino-3-dibutylamino-propyl;

[0047] 1-[1-benzyl-1-(2-phenyl-1-oxo-ethyl)-amino]-2-diethylamino-ethyl;

[0048] 1-[1-benzyl-1-(2-phenyl-1-oxo-ethyl)-amino]-2-dibutylamino-ethyl;and pharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION OF THE INVENTION

[0049] The compounds of the present invention can be administered toanyone requiring modulation of the μ receptors. Administration may beorally, topically, by suppository, inhalation, or parenterally.

[0050] The present invention also encompasses all pharmaceuticallyacceptable salts of the foregoing compounds. One skilled in the art willrecognize that acid addition salts of the presently claimed compoundsmay be prepared by reaction of the compounds with the appropriate acidvia a variety of known methods.

[0051] Various oral dosage forms can be used, including such solid formsas tablets, gelcaps, capsules, caplets, granules, lozenges and bulkpowders and liquid forms such as emulsions, solution and suspensions.The compounds of the present invention can be administered alone or canbe combined with various pharmaceutically acceptable carriers andexcipients known to those skilled in the art, including but not limitedto diluents, suspending agents, solubilizers, binders, disintegrants,preservatives, coloring agents, lubricants and the like.

[0052] When the compounds of the present invention are incorporated intooral tablets, such tablets can be compressed, tablet triturates,enteric-coated, sugar-coated, film-coated, multiply compressed ormultiply layered. Liquid oral dosage forms include aqueous andnonaqueous solutions, emulsions, suspensions, and solutions and/orsuspensions reconstituted from non-effervescent granules, containingsuitable solvents, preservatives, emulsifying agents, suspending agents,diluents, sweeteners, coloring agents, and flavoring agents. When thecompounds of the present invention are to be injected parenterally, theymay be, e.g., in the form of an isotonic sterile solution.Alternatively, when the compounds of the present invention are to beinhaled, they may be formulated into a dry aerosol or may be formulatedinto an aqueous or partially aqueous solution.

[0053] In addition, when the compounds of the present invention areincorporated into oral dosage forms, it is contemplated that such dosageforms may provide an immediate release of the compound in thegastrointestinal tract, or alternatively may provide a controlled and/orsustained release through the gastrointestinal tract. A wide variety ofcontrolled and/or sustained release formulations are well known to thoseskilled in the art, and are contemplated for use in connection with theformulations of the present invention. The controlled and/or sustainedrelease may be provided by, e.g., a coating on the oral dosage form orby incorporating the compound(s) of the invention into a controlledand/or sustained release matrix.

[0054] Specific examples of pharmaceutically acceptable carriers andexcipients that may be used to formulate oral dosage forms, aredescribed in the Handbook of Pharmaceutical Excipients, AmericanPharmaceutical Association (1986), incorporated by reference herein.Techniques and compositions for making solid oral dosage forms aredescribed in Pharmaceutical Dosage Forms: Tablets (Lieberman, Lachmanand Schwartz, editors) 2nd edition, published by Marcel Dekker, Inc.,incorporated by reference herein. Techniques and compositions for makingtablets (compressed and molded), capsules (hard and soft gelatin) andpills are also described in Remington's Pharmaceutical Sciences (ArthurOsol, editor), 1553B1593 (1980), incorporated herein by reference.Techniques and composition for making liquid oral dosage forms aredescribed in Pharmaceutical Dosage Forms: Disperse Systems, (Lieberman,Rieger and Banker, editors) published by Marcel Dekker, Inc.,incorporated herein by reference.

[0055] When the compounds of the present invention are incorporated forparenteral administration by injection (e.g., continuous infusion orbolus injection), the formulation for parenteral administration may bein the form of suspensions, solutions, emulsions in oily or aqueousvehicles, and such formulations may further comprise pharmaceuticallynecessary additives such as stabilizing agents, suspending agents,dispersing agents, and the like. The compounds of the invention may alsobe in the form of a powder for reconstitution as an injectableformulation.

[0056] The dose of the compounds of the present invention is dependentupon the affliction to be treated, the severity of the symptoms, theroute of administration, the frequency of the dosage interval, thepresence of any deleterious side-effects, and the particular compoundutilized, among other things.

[0057] The following examples illustrate various aspects of the presentinvention, and are not to be construed to limit the claims in any mannerwhatsoever.

EXAMPLES 1-3

[0058] 1-benzylamino-3-dibutylamino-propyl (Example 1);

[0059] 1-[1-benzyl-1-(2-phenyl-1-oxo-ethyl)-amino]-2-dibutylamino-ethyl(Example 2); and

[0060] 1-[1-benzyl-1-(2-phenyl-1-oxo-ethyl)-amino]-2-diethylamino-ethyl(Example 3).

[0061] The above compounds were synthesized according to the followingsynthetic scheme and general procedure:

[0062] Compound 3 (Example 1)

[0063] To a solution of benzaldehyde (1, 3.1 g, 29.5 mmol) in anhydrousmethanol was added 3-(dibutylamino)propylamine (2, 5 g, 26.8 mmol).After stirring 1 h in the presence of 3 Å molecular sieves, sodiumborohydride (1.0 g, 26.8 mmol) was added. After stirring another 16hours, the reaction was filtered, and the sieves were washed withdichloromethane. Water was added, and the phases were separated. Theaqueous phase was made basic by addition of 15% aqueous NaOH, and it wasthen extracted with dichloromethane. The combined organic extracts werewashed with water, washed with brine, dried with sodium sulfate, andconcentrated. Silica gel chromatography eluting with 20:2:1 hexane-ethylacetate-triethylamine provided compound 3 as a colorless oil: ¹H NMRdata (300 MHz, CDCl₃): δ 0.88 (t, 6H, J=7.0 Hz), 1.26 (m, 4H), 1.37 (m,4H), 1.64 (m, 2H), 2.35 (t, 4H, J=8.0 Hz), 2.43 (t, 2H, J=7.0 Hz), 2.64(t, 2H, J=6.8 Hz), 3.75 (s, 2H), 7.15-7.40 (m, 5H).

[0064] Compound 4 (Example 2)

[0065] To a solution of compound 3 (500 mg, 1.81 mmol) in anhydrous THFwas added phenylacetic acid (246 mg, 1.81 mmol), EDCI (520 mg, 2.71mmol), and DMAP (442 mg, 3.62 mmol), and the reaction mixture wasallowed to stir 15 h. Water and dichloromethane were added, and thelayers were separated. The aqueous phase was extracted withdichloromethane. The combined organic extracts were washed with 5% HCl,washed with saturated aqueous sodium bicarbonate, washed with water,washed with brine, dried with sodium sulfate, and concentrated. Silicagel chromatography eluting with 20:2:1 hexane-ethylacetate-triethylamine provided compound 4 as a colorless oil: ¹H NMRdata (300 MHz, CDCl₃): (2 rotamers) δ 2.20 (m, 6H), 1.25-1.90 (m, 8H),1.58 (m, 1.2H), 1.68 (m, 0.8H), 2.15 (m, 6H), 3.25 (t, 1.2H, J=7.4 Hz),3.40 (t, 0.8H, J=6.9 Hz), 3.68 (s, 0.8H), 3.80 (s, 1.2H), 4.50 (s,0.8H), 4.63 (s, 1.2H), 7.05-7.45 (m, 10H).

[0066] Compound 6 (Example 3)

[0067] To a solution of N′-benzyl-N,N-dimethylethylenediamine (5, 500mg, 2.8 mmol) in anhydrous THF was added phenylacetic acid (382 mg, 2.8mmol), EDCI (805 mg, 4.2 mmol), and DMAP (684 mg, 5.6 mmol), and thereaction mixture was allowed to stir 15 h. Water and dichloromethanewere added, and the layers were separated. The aqueous phase wasextracted with dichloromethane. The combined organic extracts werewashed with 5% HCl, washed with saturated aqueous sodium bicarbonate,washed with water, washed with brine, dried with sodium sulfate, andconcentrated. Silica gel chromatography eluting with 10:2:1 hexane-ethylacetate-triethylamine provided compound 6 as a colorless oil: ¹H NMRdata (300 MHz, CDCl₃): (2 rotamers) δ 2.15 (s, 2.4H), 2.20 (s, 3.6H),2.29 (t, 0.8H, J=6.9 Hz), 2.44 (t, 1.2H, J=7.4 Hz), 3.30 (t, 0.8H, J=6.9Hz), 3.48 (t, 1.2H, J=7.4 Hz), 3.70 (s, 1.2H), 3.81 (s, 0.8H), 4.57 (s,1.2H), 4.64 (s, 0.8H), 7.10-7.35 (m, 10H).

[0068] The general procedures disclosed above can be modified in orderto synthesize the other preferred compounds of the invention.

EXAMPLE 4

[0069] Affinity at the μ, k and δ receptors for preferred compounds wasobtained according to the following assays:

[0070] Mu, kappa or delta opioid receptor membrane solution was preparedby sequentially adding final concentrations of 0.075 μg/μl of thedesired membrane protein, 10 μg/ml saponin, 3 μM GDP and 0.20 nM[³⁵S]GTPγS to binding buffer (100 mM NaCl, 10 mM MgCl₂, 20 mM HEPES, pH7.4) on ice. The prepared membrane solution (190 μl/well) wastransferred to 96-shallow well polypropylene plates containing 10 μl of20× concentrated stock solutions of agonist prepared in DMSO. Plateswere incubated for 30 min at room temperature with shaking. Reactionswere terminated by rapid filtration onto 96-well Unifilter GF/B filterplates (Packard) using a 96-well tissue harvester (Brandel) and followedby three filtration washes with 200 μl ice-cold binding buffer (10 mMNaH₂PO₄, 10 mM Na₂HPO₄, pH 7.4). Filter plates were subsequently driedat 50° C. for 2-3 hours. Fifty μl/well scintillation cocktail(MicroScint20, Packard) was added and plates were counted in a PackardTop-Count for 1 min/well.

[0071] Data were analyzed using the curve fitting functions in GraphPadPRISM™, v. 3.0 and the results are set forth in table 1 below: TABLE 1calc K_(i) (nM) Compound μ k δ₂1-[1-benzyl-1-(2-phenyl-1-oxo-ethyl)-amino]-2- 40 3500 >10,000dibutylamino-ethyl

What is claimed is:
 1. Compounds of the formula (I):

R₁ is selected from the group consisting of a bond and C₁₋₁₀ alkyl,alkenyl or alkenylene; R₂ and R₃ are independently selected from thegroup consisting of hydrogen and C₁₋₁₀ alkyl, alkenyl or alkenylene R₄is selected from the group consisting of a bond and C₁₋₁₀ alkyl, alkenylor alkenylene, said C₁₋₁₀ alkyl, alkenyl or alkenylene optionallysubstituted with 1-3 halogen or oxo groups; R₅ is selected from thegroup consisting of hydrogen, a 5 or 6 membered aromatic orheteroaromatic group, and a C₃₋₁₂ cycloalkyl; R₆ is selected from thegroup consisting of C₁₋₁₀ alkyl, C₃₋₁₂ cycloalkyl and halogen; and N isan integer from 0-3; and pharmaceutically acceptable salts thereof.
 2. Acompound of claim 1 wherein R₁ is selected from methyl or ethyl.
 3. Acompound of claim 1 wherein R₂ is selected from methyl, ethyl, propyland butyl.
 4. A compound of claim 1 wherein R₄ is selected from a bond,methyl or ethyl, wherein the methyl and ethyl are optionally substitutedwith an oxo group.
 5. A compound of claim 1 wherein R₅ is phenyl.
 6. Acompound of claim 1 selected from 1-benzylamino-3-dibutylamino-propyl;1-[1-benzyl-1-(2-phenyl-1-oxo-ethyl)-amino]-2-diethylamino-ethyl;1-[1-benzyl-1-(2-phenyl-1-oxo-ethyl)-amino]-2-dibutylamino-ethyl; andpharmaceutically acceptable salts thereof.
 7. A pharmaceuticalcomposition comprising a compounds of claim 1 and at least onepharmaceutically acceptable excipient.
 8. A method of treating paincomprising administering to a patient in need thereof, an effectiveamount of a compound according to claim 1 .
 9. A method of modulating apharmacological response from the μ receptor comprising administering aneffective amount of a compound according to claim 1 .
 10. A method ofreducing side effects associated with the administration of opioidanalgesics in a human patient comprising administering to said humanpatient an analgesically effective amount of a non-opioid compound whichexhibits a binding affinity specificity for the μ receptor as comparedto the ° 2 receptor (K_(l) (nM) at the δ₂ receptor/K_(i) (nM) at the μreceptor) of greater than about 250.